Cone photoreceptor cells initiate vision in daytime, operating in light intensities that saturate rods and render them useless to the visual system. The ability of cones to escape saturation relies in large part upon specializations of proteins, including cone opsins, within the cone phototransduction cascade that function in synergy to preserve inward cGMP-sensitive current in strong light. During their biosynthesis, cone opsins have a surprising need for the visual chromophore, 11-cis retinal, to achieve proper folding, and our preliminary data suggests that they also possess a compensating capacity for proteolytic degradation of misfolded proteins. The proposed work will lead to a comprehensive, molecularly based account of these specializations within cones, and could be used in future work to both extend the operating range of the much more numerous rods, and develop strategies that facilitate the generation of properly folded opsins or increase the capacity to degrade misfolded opsins. PUBLIC HEALTH RELEVANCE: This research will provide novel, fundamental insights into the mechanisms of daytime vision, and into the mechanisms that govern the normal folding of the proteins that initiate daytime vision, the cone opsins, whose misfolding is implicated in cone- and cone-rod dystrophies. This research addresses two of the objectives recommended by the Retinal Diseases Panel (http://www.nei.nih.gov/strategicplanning/np_retinal.asp#obj) of the NEI, which are to "Use both molecular and physiological approaches to study light adaptation in photoreceptors, with particular emphasis on the visual cycle ..." and " Understand the cell biology of cones, including outer segment renewal and shedding, the phototransduction cascade, retinoid metabolism, opsin trafficking, and the regulation of gene expression for cone pigments." (http://www.nei.nih.gov/strategicplanning/np_retinal.asp)